EP1612224A1 - Nouvel anticorps monoclonal stimulant ou blocquant la thyroide, les séquences peptidiques correspondant à ses régions variables, et leur utilisation dans le diagnostic ou en médecine préventive et thérapeutique. - Google Patents

Nouvel anticorps monoclonal stimulant ou blocquant la thyroide, les séquences peptidiques correspondant à ses régions variables, et leur utilisation dans le diagnostic ou en médecine préventive et thérapeutique. Download PDF

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EP1612224A1
EP1612224A1 EP04015239A EP04015239A EP1612224A1 EP 1612224 A1 EP1612224 A1 EP 1612224A1 EP 04015239 A EP04015239 A EP 04015239A EP 04015239 A EP04015239 A EP 04015239A EP 1612224 A1 EP1612224 A1 EP 1612224A1
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Prior art keywords
antibodies
seq
iri
tshr
fragments
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EP1612224B1 (fr
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Andreas Dr. Bergmann
Nils G. Morgenthaler
Gilbert Vassart
Sabine Costagliola
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BRAHMS GmbH
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BRAHMS GmbH
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Priority to ES04015239T priority Critical patent/ES2382627T3/es
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Priority to AT04015239T priority patent/ATE548387T1/de
Priority to EP04015239A priority patent/EP1612224B1/fr
Priority to JP2007518492A priority patent/JP4980901B2/ja
Priority to PCT/EP2005/006500 priority patent/WO2006002774A1/fr
Priority to US11/570,951 priority patent/US8029790B2/en
Publication of EP1612224A1 publication Critical patent/EP1612224A1/fr
Priority to US13/181,170 priority patent/US9040670B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/76—Human chorionic gonadotropin including luteinising hormone, follicle stimulating hormone, thyroid stimulating hormone or their receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the TSHr can also be activated by autoantibodies directed against its ectodomain (1). This is the immediate cause of thyrotoxicosis and thyroid hyperplasia in patients with Graves' disease (5,6).
  • hTSHr human TSHr
  • TSHr variants from other mammals, numerous antibodies were generated in different animals against the complete TSHr or its partial sequences, but for a long time antibodies having thyroid stimulating properties and being agonists of the TSHr remained elusive.
  • the present invention provides, inter alia, a novel class of well-defined mAbs against the TSHr which fulfill the above requirements, and which have other properties and advantages which become apparent for a skilled person reading the following description.
  • the invention therefore, according to one of its main aspects provides monoclonal antibodies (mAbs) according to claim 1, which monoclonal antibodies (mAbs) in accordance with claims 2 and 4 to 8 can have thyroid stimulating activity (TSAb), or in accordance with claims 3 and 9 can be thyroid blocking antibodies.
  • mAbs monoclonal antibodies
  • TSAb thyroid stimulating activity
  • They are obtainable by genetic immunization of mice against the human TSH receptor (hTSHr), selection of mice scoring positive for the presence of antibodies stimulating or blocking the hTSHr, hybridoma generation using spleen cells of selected mice, and expansion, testing and selection of hybridoma clones producing mAbs having thyroid stimulating or blocking activity.
  • Blocking mAbs i.e. mAbs having thyroid blocking activity (mTBAb) and behaving as antagonists of the human TSHr, preferably
  • agonist or “full agonist”
  • cAMP production a bioassay by bovine TSH (saturating concentration) on cells expressing the hTSHr.
  • Antist usually means more than 20%, more usually 40% or more, “full agonist” 80% or more of the activity of bovine TSH.
  • the epitopes of IRI-SAb2 and IRI-SAb3 were precisely mapped, at the amino acid level, to the aminoterminal portion of the concave portion of the horseshoe structure of TSHr ectodomain. They overlap tightly with each other and, surprisingly, with the epitope of a mAb with blocking activity (1H7).
  • TSAb activity was measured using CHO cells expressing the hTSHr [JP26 (17)], as described (18). Duplicate samples were assayed in all experiments; results are expressed as pmoles cAMP/ml.
  • Selected mAbs and Fabs were purified by Sepharose-protein A affinity chromatography (ImmunoPureTM Fab preparation Kit, Pierce, Perbio Science, Belgium) and tested for their ability to stimulate cAMP production using JP26 CHO cells in normal isotonic medium (see above).
  • buffer A (20 mM Hepes-NaOH, pH 7.5, 50 mM NaCl, 1% BSA, 10% glycerol, 2 mg/ml mouse IgG
  • Graves' disease (GD) sera were obtained from blood donors recruited for the development of in vitro diagnostics, which was approved by a national ethical committee. Sera from patients with autoimmune thyroid disease, who were clinically hypothyroid but contained high levels of TBII, were a kind gift from Dr Daphne Khoo (Singapore General Hospital). Written consent was given by all blood donors.
  • T4 Total T4 was measured with a commercial kit (T4 mAb, ICN pharmaceuticals, New York, USA). TSH was measured as previously described (21).
  • mice Four days post injection with purified mAbs, mice were exsanguinated by cardiac puncture under Nembutal anesthesia. The thyroid glands were removed and processed for light microscopy and immunohistochemistry. Frozen sections were subjected to immunoperoxidase staining using monoclonal antibodies specific for CDR5RA positive immune cells and Mac-1 positive macrophages cells, as previously described (22) .
  • a CDR R/S ratio > 2,9 (calculated for somatic mutations occurring randomly in a gene encoding a protein whose structure need not be preserved) is indicative of antigen driven maturation of the antibodies, whereas a lower FR R/S mutation ratio ( ⁇ 2.9) reflects the negative pressure of structural components that need to be conserved (24).
  • mice Twenty female NMRI mice were immunized against the human TSHr following the protocol of genetic immunization described previously (12). Mice were bled eight weeks after the first DNA injection and antibodies against TSHr were detected by FACS in all sera from immunized mice, with values ranging from 20 ⁇ 2.5 AFU to 91 ⁇ 7 AFU (control values: 6 ⁇ 0.82 AFU). TBII activity was similarly present in all sera from immunized mice, values ranging from 42 to 92 % inhibition of labelled TSH binding (control mice: 2 ⁇ 0.5 %). TSAb activity was detectable in only five sera, with cAMP values higher than 5 pmoles/ml (controls mice: 0.77 ⁇ 0.15 pmoles/ml). Three mice showed total T4 significantly higher than controls (>4.5 ⁇ g/dl). Mouse 42, positive in all four assays and displaying the highest values in TBII, TSAb and total T4 was selected for hybridoma fusion.
  • IRI-SAb2 and IRI-SAb3 were tested for their ability to stimulate cAMP production in JP26 cells incubated in normal salt medium.
  • a concentration-dependent increase in cAMP production was observed in both cases, with maximum stimulations of 131-fold and 105-fold the basal cAMP values for IRI-SAb2 and IRI-SAb3, respectively ( Figure 1A).
  • These values represented 98 % and 80 %, respectively, of the maximum stimulation generated in the same experiment by a saturating concentration of bovine TSH (100 mIU/ml).
  • EC 50 were 2,75 ⁇ 0,25 nM and 16,5 ⁇ 3,5 nM for IRI-SAb2 and IRI-SAb3, respectively.
  • IRI-SAb2 IRI-SAb3 and 1H7 competed with TSH binding, and the concentrations required to displace 50 % of the 125 I-labeled TSH were 2 ⁇ 0,5 nM (0,3 ⁇ 0,075 ⁇ g/ml), 3,3 ⁇ 0,2 nM (0,5 ⁇ 0,03 ⁇ g/ml), and 2,6 ⁇ 0,2 nM (0,4 ⁇ 0,03 ⁇ g/ml), respectively.
  • IRI-SAb1 was poorly effective and at 10 ⁇ g/ml (66 nM), less than 5 % of the 125 I-labeled TSH was displaced.
  • the purified antibodies were subsequently labelled with acridinium ester and used in saturation experiments on hTSHr coated tubes.
  • the K d of the previously described mAb IRI-SAb1 was 2 x 10 -8 M.
  • the binding affinity of IRI-SAb2, IRI-SAb3 and 1H7 was in the 10 -10 M range, but biphasic saturation curves were observed (K d1 : 0,7 x 10 -10 M, 2,8 x 10 -10 M, 1,2 x 10 -10 M, respectively.
  • K d2 12,3 x 10 -10 M, 19,6 x 10 -10 M, 13,3 x 10 -10 M, respectively).
  • Kds were similar to that of bovine TSH (K d1 : 0, 2 x 10 -10 M, K d2 : 4,1 x 10 -10 M) (25) and a recently published human monoclonal antibody with TSAb properties (K d : 5 x 10 -10 M) (14).
  • the two different dissociation constants exhibited by IRI-SAb2, IRI-Sab3 and 1H7 for the TSHr could be interpreted as reflecting a heterogenous preparation of TSHr (partially denatured) on the coated tubes.
  • the dissociation constants K d of the novel antibodies according to the present invention when measured in saturation experiments on tubes coated with a recombinant human TSHr preparation, are in the range of about 20x10 -10 M to about 0,5x10 -10 M.
  • the four mAbs labeled with acridinium ester were used as binding tracers on hTSHr coated tubes (20). Competition was assayed with the sera from 104 euthyroid control subjects, 100 patients with Graves' disease, 8 patients scoring positive in a TSH blocking activity (TBAb) assay, and 20 TBII negative patients with Hashimoto's disease. All these sera were also evaluated in a TSH-TRAK assay (19). Except for IRI-SAb1, all mAbs were efficiently and significantly competed for by autoantibodies from Graves' disease, or TBAb positive patients, when compared to control subjects or Hashimoto's patients ( Figure 2).
  • the epitope of IRI-SAb2 included a series of nine X residues belonging to LRR1, 2 and 3 ( Figure 4A). Interestingly, except for I 60 (X 4 of LRR1), none of these residues was able to affect recognition of the constructs by the antibody, when mutated in isolation. In contrast the three triple mutants (X 2,3,4 of LRR1, X 2,3,5 of LRR2 and X 2,3,4 of LRR3) were not recognized anymore by IRI-SAb2. Mutations "en bloc" of residues X 1,2,3,4,5 of LRR4 to 6, did not impair the interaction of IRI-SAb2 with the TSHr.
  • the epitope of IRI-SAb3 included X residues belonging to LRR1 to LRR6 ( Figure 4B). Contrary to the situation with IRI-SAb2, many residues completely abolished recognition of TSHr by IRI-SAb3 when mutated individually: I 60 and E 61 (X 4 and X 5 of LRR1), Y 82 and I 85 (X 3 and X 5 of LRR2), E 107 and R 109 (X 3 and X 4 of LRR3), E 157 (X 3 of LRR5), and K 183 (X 3 of LRR6). Only in LRR4, was the simultaneous substitution of residues X 2,3,4 necessary to impair the interaction. Mutations of all X 1,2,3,4,5 residues of LRR 7, 8 and 9 did not impair the interaction of IRI-SAb3 with the TSHr.
  • the epitope of mAb 1H7 included X residues belonging to LRR1 to LRR4 ( Figure 4C). Residues which fully impaired the recognition of TSHr when mutated individually were: T 56 and K 58 (X 2 and X 3 of LRR1), R 80 and Y 82 (X 2 and X 3 of LRR2), R 109 (X 4 of LRR3). Similar to the observation with IRI-SAb3, simultaneous mutation of X 2,3,4 residues of LRR4 was necessary to impair the interaction of 1H7 with TSHr. Mutations, in combination, of residues X 1,2,3,4,5 of LRR5 and LLR6 were without effect.
  • IRI-SAb1 recognizes the human TSHr very efficiently and, to a lesser extent, the sheep receptor. It did not bind to TSHr from rat, cat or dog nor to the mouse receptor.
  • IRI-SAb2 and IRI-SAb3 were then tested for their ability to stimulate the mouse TSHr in normal-salt medium (Figure 6B).
  • a concentration-dependent increase in cAMP production was observed, with a maximum stimulation of 22 fold the basal cAMP values for the two antibodies. This represented 134% of the maximum stimulation generated in the same experiment by a saturating concentration of bovine TSH.
  • EC 50 were 1,3 ⁇ 0,66 nM for IRI-SAb2 and 3,8 ⁇ 0,48 nM for IRI-SAb3.
  • IRI-SAb2 and IRI-SAb3 were then assessed by intravenous injection of IgGs in mice.
  • Two days after injection (Figure 7A), the total T4 levels were almost double in mice injected with IRI-SAb2 or IRI-SAb3, when compared to the control groups.
  • TSH levels in the control groups were very heterogeneous: only 2 mice out of the 15 controls showed TSH values below 10 mIU/L ( Figure 7C).
  • T4 levels remained stably high four days post injection ( Figure 7B) and TSH values below 10 mIU/L ( Figure 7D).
  • Figure 7E We subsequently investigated the short and long time responses to TSAb, in a group of mice injected with IRI-SAb2 ( Figure 7E). 8 hours post injection, T4 levels were already elevated (8,18 ⁇ 0,83 ⁇ g/dl). These levels decreased slightly at 24 hours and had almost normalized seven days post injection, which is consistent with the reported serum half life of mouse IgG2a (6-8 days) .
  • thyroid morphology was considerably modified as compared to control mice.
  • the follicular epithelial layers were often made of hypertrophic cells, with irregular apical poles protruding into the colloid. Numerous necrotic thyrocytes were also detected, shedded in some follicular lumina, which is considered a sign of a toxic effect of the acute hyperstimulation. Dying thyrocytes, with picnotic eccentric nuclei were also observed in the some follicles. An extended infiltrate throughout the gland was observed. These cells, in the interstitium, were immunohistochemically typed as CD45+ immune cells and numerous Mac-1+ positive macrophages were observed between the thyrocytes and inside the colloid.
  • Hybridomas producing the two stimulating antibodies IRI-SAb2 and IRI-SAb3, and the blocking antibody 1H7 were deposited on May 27, 2004 with DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1b, D-38124 Braunschweig and were allotted the Accession Numbers (Eingangsnow) DSM ACC2664; DSM ACC2662 and DSM ACC2663 respectively.
  • the International Receipt Forms of the International Depositary Authority DSMZ are enclosed.
  • IRI-SAb2 is a full agonist of the human TSHr
  • Dimerization/oligomerization of GPCRs is a subject of intense current interest. Despite some contradictory indications there is however no strong evidence that modification of the di/oligomerization status of GPCRs or GPHRs is involved in the activation process, per se. Our results with Fab fragments of IRI-SAb2 and IRI-SAb3 confirm earlier results with TSAbs from patients (1,30) that monovalent antibodies are as active as intact IgGs, ruling out that activation by these antibodies would be secondary to forced dimerization or aggregation.
  • IRI-SAb2 and IRI-SAb3 will be administered chronically to naive mice, will show whether overstimulation of the glands may, by itself, lead to an autoimmune reaction with generation of anti-thyroglobulin and/or anti-thyroperoxidase autoantibodies.
  • Blocking mAb 1H7 is of interest as a potential alternative for a use (therapeutical method) in the treatment of hyperthyroidism in accordance with DE 199 07 094 Cl and corresponding WO 00/49050 A2/A3. Accordingly, the present invention also covers the use of such blocking mAb for the preparation of a medicament for treating hyperthyroidism.
  • IRI-SAb2 and IRI-SAb3 may qualify IRI-SAb2 and IRI-SAb3, as well as 1H7, as tracers in in vitro immunoassays or with application in the imaging or, linked to a radiolabel or a cytotoxic agent or toxine, for the destruction especially of non-iodine uptaking metastases of less differentiated thyroid cancers.
EP04015239A 2004-06-29 2004-06-29 Nouvel anticorps monoclonal stimulant ou blocquant la thyroide, les séquences peptidiques correspondant à ses régions variables, et leur utilisation dans le diagnostic ou en médecine préventive et thérapeutique. Active EP1612224B1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AT04015239T ATE548387T1 (de) 2004-06-29 2004-06-29 Neue monoklonale schilddrüsen-stimulierende oder -blockierende antikörper, korrespondierende peptidesquenzen ihrer variablen regionen, und deren verwendung in diagnostik, präventiver und therapeutischer medizin
EP04015239A EP1612224B1 (fr) 2004-06-29 2004-06-29 Nouvel anticorps monoclonal stimulant ou blocquant la thyroide, les séquences peptidiques correspondant à ses régions variables, et leur utilisation dans le diagnostic ou en médecine préventive et thérapeutique.
ES04015239T ES2382627T3 (es) 2004-06-29 2004-06-29 Nuevos anticuerpos monoclonales estimuladores o bloqueadores de la tiroides, secuencias peptídicas que corresponden a sus regiones variables, y sus usos en medicina diagnóstica, preventiva y terapéutica
PCT/EP2005/006500 WO2006002774A1 (fr) 2004-06-29 2005-06-16 Nouveaux anticorps monoclonaux stimulant ou bloquant la thyroide, sequences de peptides correspondant a leurs regions variables et leurs utilisations en medecine diagnostique, preventive ou therapeutique
JP2007518492A JP4980901B2 (ja) 2004-06-29 2005-06-16 新規なモノクローナル甲状腺刺激または阻害抗体、その可変領域に相当するペプチド配列、ならびに診断用医薬、予防用医薬および治療用医薬におけるそれらの使用
US11/570,951 US8029790B2 (en) 2004-06-29 2005-06-16 Monoclonal thyroid stimulating or blocking antibodies, peptide sequences corresponding to their variable regions, and their uses in diagnostic, preventive and therapeutic medicine
US13/181,170 US9040670B2 (en) 2004-06-29 2011-07-12 Monoclonal thyroid stimulating or blocking antibodies, peptide sequences corresponding to their variable regions, and their uses in diagnostic, preventive and therapeutic medicine

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Application Number Priority Date Filing Date Title
EP04015239A EP1612224B1 (fr) 2004-06-29 2004-06-29 Nouvel anticorps monoclonal stimulant ou blocquant la thyroide, les séquences peptidiques correspondant à ses régions variables, et leur utilisation dans le diagnostic ou en médecine préventive et thérapeutique.

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EP1612224A1 true EP1612224A1 (fr) 2006-01-04
EP1612224B1 EP1612224B1 (fr) 2012-03-07

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US (2) US8029790B2 (fr)
EP (1) EP1612224B1 (fr)
JP (1) JP4980901B2 (fr)
AT (1) ATE548387T1 (fr)
ES (1) ES2382627T3 (fr)
WO (1) WO2006002774A1 (fr)

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US8350012B2 (en) 2007-01-25 2013-01-08 Cedars-Sinai Medical Center Inverse agonist monoclonal antibody that suppresses thyrotropin receptor constitutive activity
JP5676316B2 (ja) * 2010-03-09 2015-02-25 富士フイルム株式会社 ヒトｔｓｈ及び犬ｔｓｈに対する抗体
CA2800311A1 (fr) * 2010-05-11 2011-11-17 Aveo Pharmaceuticals, Inc. Anticorps anti-fgfr2
US8785603B2 (en) 2011-05-20 2014-07-22 Siemens Healthcare Diagnostics Inc. Antibodies to 25-hydroxyvitamin D2 and D3 and uses thereof
CN102735850A (zh) * 2012-07-16 2012-10-17 天津医科大学总医院 定量检测人血清促甲状腺素受体抗体的酶联免疫分析试剂盒及检测方法
CN105189558A (zh) * 2013-05-02 2015-12-23 豪夫迈·罗氏有限公司 无岩藻糖基化CD20抗体与CD79b抗体-药物缀合物的组合疗法
CN111690680A (zh) * 2020-06-10 2020-09-22 成都和同易创生物科技有限公司 Tbab人源单克隆抗体重组载体、重组抗体及其制备方法
CN111647624A (zh) * 2020-06-10 2020-09-11 成都和同易创生物科技有限公司 Tsab人源单克隆抗体重组载体、重组抗体及其制备方法

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WO1995023865A1 (fr) * 1994-03-03 1995-09-08 Genentech, Inc. Anticorps monoclonaux anti-il-8 pour le traitement des troubles
WO2000049050A2 (fr) * 1999-02-19 2000-08-24 B.R.A.H.M.S Diagnostica Gmbh Utilisation d'anticorps de blocage agissant contre le recepteur de tsh pour traiter l'hyperthyroidie, et anticorps monoclonaux faisant l'objet d'une telle utilisation
WO2000061637A1 (fr) * 1999-04-14 2000-10-19 Smithkline Beecham Corporation Anticorps du recepteur d'erythropoietine
WO2003018632A2 (fr) * 2001-08-23 2003-03-06 Rsr Limited Regions des epitopes du recepteur de la thyrotrophine (tsh) leurs utilisations et leurs anticorps
WO2004050708A2 (fr) * 2002-11-29 2004-06-17 Rsr Limited Partenaires de liaison du recepteur de la thyrotropine et utilisations de ceux-ci

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US8029790B2 (en) 2011-10-04
US20090012268A1 (en) 2009-01-08
ES2382627T3 (es) 2012-06-12
US20120253019A1 (en) 2012-10-04
US9040670B2 (en) 2015-05-26
EP1612224B1 (fr) 2012-03-07
JP2008509887A (ja) 2008-04-03
JP4980901B2 (ja) 2012-07-18
WO2006002774A1 (fr) 2006-01-12
ATE548387T1 (de) 2012-03-15

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